Amiodarone-induced thyrotoxicosis (AIT) occurs in both abnormal (type I) and apparently normal (type II) thyroid glands due to iodine-induced excessive thyroid hormone synthesis in patients with nodular goiter or latent Graves' disease (type I) or to a thyroid-destructive process caused by amiodarone or iodine (type II). Twenty-four consecutive AIT patients, 12 type I and 12 type II, were evaluated prospectively. Sex, age, severity of thyrotoxicosis, and cumulative amiodarone dose were similar. Type II patients had higher serum interleukin-6 (IL-6; median, 440 vs. 173 fmol/L; P < 0.001), but lower serum thyroglobulin levels. Several weeks of thionamide therapy in eight type II or prolonged glucocorticoid administration in two type I patients had previously failed to control hyperthyroidism. Type II patients were given prednisone (initial dose, 40 mg/day) for 3 months and achieved normal free T3 and IL-6 after an average of 8 and 6 days, respectively. Exacerbation of thyrotoxicosis with increased serum IL-6 values, observed in 4 patients while tapering steroid, was promptly corrected by increasing it. Type I patients, given methimazole (30 mg/day) and potassium perchlorate (1 g/day), achieved normal free T3 and IL-6 concentrations after an average of 4 weeks. Exacerbation of thyrotoxicosis with markedly increased IL-6 was controlled by prednisone in 3 of 4 cases. Distinction of different forms of AIT is essential for its successful management. Type II AIT should be treated with glucocorticoids; type I AIT should be treated with methimazole and potassium perchlorate. Exacerbation of thyrotoxicosis, which may occur in both forms and is probably related to destructive processes, should be controlled by the addition/increase in glucocorticoids.

Objective: Thyroid blood flow is greatly enhanced in untreated Graves' disease, but it is not known whether it is due to thyroid hormone excess or to thyroid hyperstimulation by TSH-receptor antibody. To address this issue in vivo patients with different thyroid disorders were submitted to color flow doppler sonography (CFDS). Subjects and methods:We investigated 24 normal subjects, and 78 patients with untreated hyperthyroidism (49 with Graves' hyperthyroidism, 24 with toxic adenoma, and 5 patients with TSH-secreting pituitary adenoma (TSHoma)), 19 patients with thyrotoxicosis (7 with thyrotoxicosis factitia, and 12 with subacute thyroiditis), 37 euthyroid patients with goitrous Hashimoto's thyroiditis, and 21 untreated hypothyroid patients with Hashimoto's thyroiditis. Results: Normal subjects had CFDS pattern 0 (absent or minimal intraparenchimal spots) and mean intraparenchimal peak systolic velocity (PSV) of 4.8 Ϯ 1.2 cm/s. Patients with spontaneous hyperthyroidism due to Graves' disease, TSHoma, and toxic adenoma had significantly increased PSV (P < 0.0001, P = 0.0004, P < 0.0001 respectively vs controls) and CFDS pattern. Patients with Graves' disease had CFDS pattern II (mild increase of color flow doppler signal) in 10 (20%) and pattern III (marked increase) in 39 cases (80%). Mean PSV was 15 Ϯ 3 cm/s. Patients with toxic adenoma had CFDS pattern I (presence of parenchymal blood flow with patchy uneven distribution) in 2 (8%), pattern II in 16 (70%) and pattern III in 5 (22%). Mean PSV was 11 Ϯ 2.4 cm/s. Patients with TSHoma showed CFDS pattern I in one case (20%) and pattern II in 4 (80%). Mean PSV was 14.8 Ϯ 4.2 cm/s. Patients with thyrotoxicosis had normal PSV (4.2 Ϯ 1.1 cm/s in subacute thyroiditis, 4 Ϯ 0.8 cm/s in thyrotoxicosis factitia, P = not significant vs controls) and CFDS pattern 0. Untreated euthyroid patients with goitrous Hashimoto's thyroiditis had CFDS pattern 0, and mean PSV (4.3 Ϯ 0.9 cm/s; P = not significant vs controls). Untreated hypothyroid patients with goitrous Hashimoto's thyroiditis had CFDS pattern I in 14 cases (67%), pattern II in 4 (19%) and pattern 0 in 3 (14%) and mean PSV (5.6 Ϯ 1.4 cm/s) was higher than that of controls (P = 0.026). Conclusions: An increase in both intrathyroidal vascularity and blood velocity was observed in patients with spontaneous hyperthyroidism but not in thyrotoxicosis due to either ingestion of thyroid hormones or to a thyroidal destructive process. The slightly increased vascularity and blood velocity observed in patients with hypothyroid Hashimoto's thyroiditis suggests that thyroid stimulation by either TSH-receptor antibody or TSH is responsible for the increased thyroid blood flow.

Amiodarone-induced thyrotoxicosis (AIT) occurs both in abnormal thyroid glands (nodular goiter, latent Graves' disease) (type I AIT) or in apparently normal thyroid glands (type II AIT). Differentiation of the two forms is crucial, because type I AIT responds well to methimazole and potassium perchlorate combined treatment, whereas type II AIT is effectively managed by glucocorticoids. Differential diagnosis is often difficult, although thyroid radioactive iodine uptake is usually low-to-normal in type I and low-suppressed in type II, and serum interleukin-6 levels are normal/slightly elevated in type I, markedly elevated in type II. Color flow Doppler sonography (CFDS) is a technique that shows intrathyroidal blood flow and provides real-time information on thyroid morphology and hyperfunction. To investigate the usefulness of CFDS in differentiating the two types of AIT, 27 consecutive AIT patients, 11 type I and 16 type II, were evaluated by CFDS before starting antithyroid treatment. Gender, age, severity of thyrotoxicosis, and cumulative amiodarone dose were similar in the two groups. All type II AIT patients had a CFDS pattern 0 (ie, absent vascularity), in agreement with the pathogenesis of the disease, due to thyroid damage. Likewise, nine patients with subacute thyroiditis, another destructive process of the thyroid gland, also had a CFDS pattern 0. Eleven patients with type I AIT had a CFDS pattern ranging from pattern I (presence of parenchymal blood flow with patchy uneven distribution) (7 patients, 64%) to pattern II (ie, mild increase of color flow Doppler signal with patchy distribution) (1 patient, 9%) and pattern III (markedly increased color flow Doppler signal with diffuse homogeneous distribution)(3 patients, 27%), similar to that found in patients with untreated Graves' disease patients, thus indicating a hyper-functioning gland. Control subjects and euthyroid patients under long-term amiodarone treatment had absent thyroid hypervascularity and a CFDS pattern 0. These findings demonstrate that CFDS distinguishes type I and II AIT. Because of its rapidity and noninvasive features, CFDS represents a valuable tool for a quick differentiation between the two types of AIT. This can avoid any delay in initiating the appropriate treatment for a rapid control of thyrotoxicosis in patients whose tachyarrhythmias or other cardiac disorders make thyroid hormone excess extremely deleterious.

Objective: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. Materials and methods: The reporter construct ME-TRE-TK-CAT or TSHb-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHb genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRb into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)b. Results: Addition of 1 mmol/l T 4 or T 3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5-and 12.5-fold respectively. Amiodarone or DEA (1 mmol/l) increased CAT activity by 1.4-and 3.4-fold respectively. Combination of DEA with T 4 or T 3 increased CAT activity by 9.4-and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRb was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 mmol/l DEA decreased the T 3 -dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T 3 ), whereas amiodarone was ineffective. Addition of 1 mmol/l DEA to T 3 -containing medium reduced the T 3 ±TR-mediated down-regulation of TSH-TRE to 55%. Conclusions: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T 3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.